ChREBP mediates glucose-stimulated pancreatic [beta]-cell proliferation

Glucose stimulates rodent and human [beta]-cell replication, but the intracellular signaling mechanisms are poorly understood. Carbohydrate response element-binding protein (ChREBP) is a lipogenic glucose-sensing transcription factor with unknown functions in pancreatic [beta]-cells. We tested the hypothesis that ChREBP is required for glucose-stimulated [beta]-cell proliferation. The relative expression of ChREBP was determined in liver and [beta]-cells using quantitative RT-PCR (qRT-PCR), immunoblotting, and immunohistochemistry. Loss- and gain-of-function studies were performed using small interfering RNA and genetic deletion of ChREBP and adenoviral overexpression of ChREBP in rodent and human [beta]-cells. Proliferation was measured by 5-bromo-2'-deoxyuridine incorporation, [[sup.3]H]thymidine incorporation, and fluorescence-activated cell sorter analysis. In addition, the expression of cell cycle regulatory genes was measured by qRT-PCR and immunoblotting. ChREBP expression was comparable with liver in mouse pancreata and in rat and human islets. Depletion of ChREBP decreased glucose-stimulated proliferation in [beta]-cells isolated from [ChREBP.sup.-/-] mice, in INS-1-derived 832/13 cells, and in primary rat and human [beta]-cells. Furthermore, depletion of ChREBP decreased the glucose-stimulated expression of cell cycle accelerators. Overexpression of ChREBP amplified glucose-stimulated proliferation in rat and human [beta]-cells, with concomitant Increases in cyclin gene expression. In conclusion, ChREBP mediates glucose-stimulated proliferation in pancreatic [beta]-cells. Diabetes 61:2004-2015, 2012